@article{goetz_rockett_ren_thillainadarajah_dix_2009, title={Inhibition of Rat and Human Steroidogenesis by Triazole Antifungals}, volume={55}, ISSN={["1939-6376"]}, DOI={10.3109/19396360903234045}, abstractNote={Environmental chemicals that alter steroid production could interfere with male reproductive development and function. Three agricultural antifungal triazoles that are known to modulate expression of cytochrome P450 (CYP) genes and enzymatic activities were tested for effects on steroidogenesis using rat in vivo (triadimefon), rat in vitro (myclobutanil and triadimefon), and human in vitro (myclobutanil, propiconazole, and triadimefon) model systems. Hormone production was measured in testis organ cultures from untreated adult and neonatal rats, following in vitro exposure to 1, 10, or 100 μM of myclobutanil or triadimefon. Myclobutanil and triadimefon reduced media levels of testosterone by 40–68% in the adult and neonatal testis culture, and altered steroid production in a manner that indicated CYP17-hydroxylase/17,20 lyase (CYP17A1) inhibition at the highest concentration tested. Rat to human comparison was explored using the H295R (human adrenal adenocarcinoma) cell line. Following 48 h exposure to myclobutanil, propiconazole, or triadimefon at 1, 3, 10, 30, or 100 μM, there was an overall decrease in estradiol, progesterone, and testosterone by all three triazoles. These data indicate that myclobutanil, propiconazole, and triadimefon are weak inhibitors of testosterone production in vitro. However, in vivo exposure of rats to triazoles resulted in increased serum and intra-testicular testosterone levels. This discordance could be due to higher concentrations of triazoles tested in vitro, and differences within an in vitro model system lacking hepatic metabolism and neuroendocrine control.}, number={5-6}, journal={SYSTEMS BIOLOGY IN REPRODUCTIVE MEDICINE}, author={Goetz, Amber K. and Rockett, John C. and Ren, Hongzu and Thillainadarajah, Inthirany and Dix, David J.}, year={2009}, pages={214–226} }
 @article{goetz_dix_2009, title={Mode of Action for Reproductive and Hepatic Toxicity Inferred from a Genomic Study of Triazole Antifungals}, volume={110}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfp098}, abstractNote={The mode of action for the reproductive toxicity of some triazole antifungals has been characterized as an increase in serum testosterone and hepatic response, and reduced insemination and fertility indices. In order to refine our mechanistic understanding of these potential modes of action, gene expression profiling was conducted on liver and testis from male Wistar Han IGS rats exposed to myclobutanil (500, 2000 ppm), propiconazole (500, 2500 ppm), or triadimefon (500, 1800 ppm) from gestation day six to postnatal day 92. Gene expression profiles indicated that all three triazoles significantly perturbed the fatty acid, steroid, and xenobiotic metabolism pathways in the male rat liver. In addition, triadimefon modulated expression of genes in the liver from the sterol biosynthesis pathway. Although expression of individual genes were affected, there were no common pathways modulated by all three triazoles in the testis. The pathways identified in the liver included numerous genes involved in phase I-III metabolism (Aldh1a1, Cyp1a1, Cyp2b2, Cyp3a1, Cyp3a2, Slco1a4, Udpgtr2), fatty acid metabolism (Cyp4a10, Pcx, Ppap2b), and steroid metabolism (Ugt1a1, Ugt2a1) for which expression was altered by the triazoles. These differentially expressed genes form part of a network involving lipid, sterol, and steroid homeostatic pathways regulated by the constitutive androstane (CAR), pregnane X (PXR), peroxisome proliferator-activated alpha, and other nuclear receptors in liver. These relatively high dose and long-term exposures to triazole antifungals appeared to perturb fatty acid and steroid metabolism in the male rat liver predominantly through the CAR and PXR signaling pathways. These toxicogenomic effects describe a plausible series of key events contributing to the disruption in steroid homeostasis and reproductive toxicity of select triazole antifungals.}, number={2}, journal={TOXICOLOGICAL SCIENCES}, author={Goetz, Amber K. and Dix, David J.}, year={2009}, month={Aug}, pages={449–462} }
 @article{goetz_dix_2009, title={Toxicogenomic effects common to triazole antifungals and conserved between rats and humans}, volume={238}, ISSN={["1096-0333"]}, DOI={10.1016/j.taap.2009.04.016}, abstractNote={The triazole antifungals myclobutanil, propiconazole and triadimefon cause varying degrees of hepatic toxicity and disrupt steroid hormone homeostasis in rodent in vivo models. To identify biological pathways consistently modulated across multiple timepoints and various study designs, gene expression profiling was conducted on rat livers from three separate studies with triazole treatment groups ranging from 6 h after a single oral gavage exposure, to prenatal to adult exposures via feed. To explore conservation of responses across species, gene expression from the rat liver studies were compared to in vitro data from rat and human primary hepatocytes exposed to the triazoles. Toxicogenomic data on triazoles from 33 different treatment groups and 135 samples (microarrays) identified thousands of probe sets and dozens of pathways differentially expressed across time, dose, and species--many of these were common to all three triazoles, or conserved between rodents and humans. Common and conserved pathways included androgen and estrogen metabolism, xenobiotic metabolism signaling through CAR and PXR, and CYP mediated metabolism. Differentially expressed genes included the Phase I xenobiotic, fatty acid, sterol and steroid metabolism genes Cyp2b2 and CYP2B6, Cyp3a1 and CYP3A4, and Cyp4a22 and CYP4A11; Phase II conjugation enzyme genes Ugt1a1 and UGT1A1; and Phase III ABC transporter genes Abcb1 and ABCB1. Gene expression changes caused by all three triazoles in liver and hepatocytes were concentrated in biological pathways regulating lipid, sterol and steroid homeostasis, identifying a potential common mode of action conserved between rodents and humans. Modulation of hepatic sterol and steroid metabolism is a plausible mode of action for changes in serum testosterone and adverse reproductive outcomes observed in rat studies, and may be relevant to human risk assessment.}, number={1}, journal={TOXICOLOGY AND APPLIED PHARMACOLOGY}, author={Goetz, Amber K. and Dix, David J.}, year={2009}, month={Jul}, pages={80–89} }
 @article{goetz_ren_schmid_blystone_thillainadarajah_best_nichols_strader_wolf_narotsky_et al._2007, title={Disruption of testosterone homeostasis as a mode of action for the reproductive toxicity of triazole fungicides in the male rat}, volume={95}, DOI={10.1093/toxsci/kfl124}, abstractNote={Triazole fungicides associated with a range of reported male reproductive effects in experimental animals were selected to assess potential toxic modes of action. Wistar Han rats were fed myclobutanil (M: 100, 500, or 2000 ppm), propiconazole (P: 100, 500, or 2500 ppm), or triadimefon (T: 100, 500, or 1800 ppm) from gestation day 6 to postnatal day (PND) 120. One male per litter was necropsied on PND1, 22, 50, or 92. Measurements included anogenital distance (AGD) at PND0, body and organ weights, serum hormone levels, age at preputial separation (PPS), sperm morphology and motility, and fertility and fecundity. AGD was increased by the high dose of all three triazoles, indicating hypervirilization. Triadimefon delayed PPS, consistent with delayed puberty, at 1800 ppm. Relative liver weights were increased at PND1, 50, and 92 by all three triazoles. Hepatocellular hypertrophy was present at PND50 from propiconazole and triadimefon and at PND92 from all three high-dose triazole treatments. Relative pituitary weights were decreased at PND92 by middle- and high-dose myclobutanil treatment. Absolute testis weights were increased at PND1 by myclobutanil, at PND22 by myclobutanil and triadimefon, and at PND50 by propiconazole and triadimefon treatment. Relative ventral prostate weights were increased at PND92 by myclobutanil and triadimefon treatment. Serum testosterone was increased at PND50 by triadimefon and at PND92/99 by all three triazole treatments. Insemination and fertility were impaired by myclobutanil and triadimefon treatment. In addition to the reproductive system effects, total serum thyroxine levels were decreased at PND92 by high-dose triadimefon. These reproductive effects are consistent with the disruption of testosterone homeostasis as a key event in the mode of action for triazole-induced reproductive toxicity.}, number={1}, journal={Toxicological Sciences}, author={Goetz, A. K. and Ren, H. Z. and Schmid, J. E. and Blystone, C. R. and Thillainadarajah, I. and Best, D. S. and Nichols, H. P. and Strader, L. F. and Wolf, D. C. and Narotsky, M. G. and et al.}, year={2007}, pages={227–239} }
 @article{rockett_narotsky_thompson_thillainadarajah_blystone_goetz_ren_best_murrell_nichols_et al._2006, title={Effect of conazole fungicides on reproductive development in the female rat}, volume={22}, number={4}, journal={Reproductive Toxicology (Elmsford, N.Y.)}, author={Rockett, J. C. and Narotsky, M. G. and Thompson, K. E. and Thillainadarajah, I. and Blystone, C. R. and Goetz, A. K. and Ren, H. and Best, D. S. and Murrell, R. N. and Nichols, H. P. and et al.}, year={2006}, pages={647–658} }
 @article{bao_schmid_goetz_ren_dix_2005, title={A  database for tracking toxicogenomic samples and procedures}, volume={19}, number={3}, journal={Reproductive Toxicology (Elmsford, N.Y.)}, author={Bao, W. J. and Schmid, J. E. and Goetz, A. K. and Ren, H. Z. and Dix, D. J.}, year={2005}, pages={411–419} }